Multiple myeloma (MM) is the 2nd most common hematologic malignancy accounting for ~1 percent of all cancers in the Western countries. Despite recent advances in treatment options, it remains incurable with high rates of relapse and drug resistance, with a median survival of ~5 years. Although the etiology of MM is unclear, it is preceded by precursor asymptomatic plasma cell dyscrasias known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Despite the availability of clinical risk models, genomic aberrations and imaging, efforts to utilize these indices to accurately classify early stage precursor disease and monitor clinical course have not been successful. In contrast, recent advances in transcriptome sequencing offer new opportunities to characterize miRNAs as novel biomarkers, which could significantly change the paradigm of MM classification, and ultimately, management and treatment. The goal of the proposed investigation is to identify and characterize the contribution of miRNAs in serum exosomes on the presence of MM, and within the spectrum of progression, MGUS and SMM. We will test the overarching hypothesis that distinct serum exosome miRNAs will correlate with the presence of each precursor disease and myeloma phenotype and a subset of serum exosome miRNAs will correlate with the presence of all precursor disease and myeloma phenotypes relative to controls, giving rise to high priority targets important for MM risk. In addition, we hypothesize that miRNAs influence precursor disease and myeloma phenotypes by altering target gene expression. To address this hypothesis we intend to: (1) identify miRNAs associated with the presence of MM and its asymptomatic precursor states using discovery and independent replication populations and (2) characterize miRNA target genes important for the presence of MM and its asymptomatic precursor states using a whole transcriptome miRNA-mRNA approach. Direct modeling of miRNA-mRNA relationships is critical to advance our understanding of the role miRNAs in regulating post-transcriptional expression of target genes and in so doing, providing insight into biologic mechanism fundamental to disease etiology. This project leverages existing partnerships, resources and comprehensive, high quality clinical data and biospecimens collected in a network of populations to fill a critical gap in knowledge required to improve our understanding of myeloma etiology and disease states associated with progression. Such characterizations can be used to significantly transform the current paradigm for disease surveillance by advancing a set of biomarkers to target high-risk populations who may benefit from early detection and individualized clinical management.